A novel oncotherapy strategy: Direct thrombin inhibitors suppress progression, dissemination and spontaneous metastasis in non-small cell lung cancer

Bing Zhao; Mengfang Wu; Zhihuang Hu; Tianfa Wang; Jinchao Yu; Yixin Ma; Qi Wang; Yanling Zhang; Di Chen; Tianyu Li; Yaran Li; Min Yu; Huijie Wang; Wei Mo

doi:10.1111/bph.15384

A novel oncotherapy strategy: Direct thrombin inhibitors suppress progression, dissemination and spontaneous metastasis in non-small cell lung cancer

Br J Pharmacol. 2022 Nov;179(22):5056-5073. doi: 10.1111/bph.15384. Epub 2021 Feb 27.

Authors

Bing Zhao^{1

2}, Mengfang Wu^{1

2}, Zhihuang Hu^{3

4}, Tianfa Wang^{1

2}, Jinchao Yu¹, Yixin Ma^{1

2}, Qi Wang^{1

2}, Yanling Zhang^{1

2}, Di Chen^{1

2}, Tianyu Li^{1

2}, Yaran Li^{1

2}, Min Yu^{1

2}, Huijie Wang^{3

4}, Wei Mo^{1

2}

Affiliations

¹ Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, Fudan University, Shanghai, China.
² Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China.
³ Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
⁴ Department of Medical Oncology, Shanghai Cancer Center, Fudan University, Shanghai, China.

PMID: 33481255
DOI: 10.1111/bph.15384

Abstract

Background and purpose: Cancer cachexia and cancer-associated thrombosis are potentially fatal outcomes of advanced cancer. Nevertheless, thrombin expression in non-small cell lung cancer (NSCLC) primary tumour tissues and the association between prognosis of NSCLC patients remain largely unknown.

Experimental approach: Clinical pathological analysis was performed to determine the relationship between thrombin and tumour progression. Effects of r-hirudin and direct thrombin inhibitor peptide (DTIP) on cancer progression were evaluated. Western blotting, immunohistochemistry, and immunofluorescence were used to explore the inhibition mechanism of r-hirudin and DTIP. The therapeutic effect of the combination of DTIP and chemotherapy was determined.

Key results: Thrombin expression in NSCLC tissues was closely related to clinicopathological features and the prognosis of patients. Thrombin deficiency inhibited tumour progression. The novel thrombin inhibitors, r-hirudin and DTIP, inhibited cell invasion and metastasis in vitro. They inhibited tumour growth and metastasis in orthotopic lung cancer model, inhibited cell invasion, and prolonged survival after injection of tumour cells via the tail vein. They also inhibited angiogenesis and spontaneous metastases from subcutaneously inoculated tumours. The promotion by thrombin of invasion and metastasis was abolished in PAR-1-deficient NSCLC cells. r-hirudin and DTIP inhibited tumour progression through the thrombin-PAR-1-mediated RhoA and NF-κB signalling cascades via inhibiting MMP9 and IL6 expression. DTIP potentiated chemotherapy-induced growth and metastatic inhibition and inhibited chemotherapy-induced resistance in mice.

Conclusions and implications: Thrombin makes a substantial contribution, together with PAR-1, to NSCLC malignancy. The anti-coagulants, r-hirudin and DTIP, could be used in anti-tumour therapy and a combination of DTIP and chemotherapy might improve therapeutic effects.

Keywords: combination therapy; direct thrombin inhibitors; metastasis; non-small cell lung cancer; thrombin.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antineoplastic Agents*
Antithrombins
Carcinoma, Non-Small-Cell Lung* / drug therapy
Fibrinolytic Agents
Hirudins / pharmacology
Interleukin-6
Lung Neoplasms* / drug therapy
Lung Neoplasms* / secondary
Matrix Metalloproteinase 9
Mice
NF-kappa B
Neoplasm Metastasis
Thrombin

Substances

Antineoplastic Agents
Antithrombins
Fibrinolytic Agents
Hirudins
Interleukin-6
NF-kappa B
Thrombin
Matrix Metalloproteinase 9